EP2391633A1 - Process for the recovery of beta-acetylfuranoside - Google Patents
Process for the recovery of beta-acetylfuranosideInfo
- Publication number
- EP2391633A1 EP2391633A1 EP10700424A EP10700424A EP2391633A1 EP 2391633 A1 EP2391633 A1 EP 2391633A1 EP 10700424 A EP10700424 A EP 10700424A EP 10700424 A EP10700424 A EP 10700424A EP 2391633 A1 EP2391633 A1 EP 2391633A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- acf
- acetylation
- distillation
- acetylfuranoside
- weight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
Definitions
- the present invention is directed to a novel process for the recovery of further ⁇ - Acetylfuranoside ( ⁇ -ACF, ⁇ -5-deoxy-l,2,3-tri-O-acetyl-D-ribofuranose) from mother liquors and process waste streams remaining from an initial synthesis of ACF.
- ⁇ -ACF ⁇ - Acetylfuranoside
- ACF can be prepared according to well known methods, as for example described in Helvetica Chimica Acta, Vol. 65 (Nr.149), Fasc. 5, 1982, 1531.
- the synthesis of ACF leads to a racemic mixture of ⁇ - and ⁇ -ACF which can be separated by selective crystallization and thus precipitation from the reaction mixture.
- the ⁇ -ACF is the desired product, as it is a valuable starting material used in the manufacture of inter alia cytidine derivatives, such as capecitabine.
- Capecitabine is the active ingredient of the medicament XelodaTM.
- the ACF synthesis can be summarized according to the following reaction scheme 1 :
- the remaining, residual reaction mixture (mother liquor) contains about 8-15 weight-% of not precipitated ⁇ / ⁇ -Acetylfuranoside (ratio ⁇ : ⁇ is about
- the advantages of the method according to the present invention are the increase of the overall yield of ⁇ -ACF, and consequently also of capecitabine per production cycle, thereby reducing the overall production costs.
- the present method renders the entire manufacturing more environmentally friendly due to avoiding of unnecessary high amounts of chemical waste.
- the method according to the present invention can also optionally be repeated in several serially connected cycles, thereby further improving the efficacy of the present method.
- the present invention provides a method for recovery of initially not separated ⁇ -ACF from mother liquor remaining from the synthesis of ACF, wherein the ⁇ -ACF is recovered by a combination of at least one distillation method and at least one chemical reaction step.
- step a) and b) Optional repetition of step a) and b) in a sequential (clockwise) cyclic process.
- the distillation to about 60 to 80 weight-% in process step a) as described above is carried out at 1 to 3 mbar and 200 to 210 0 C heating temperature in a continuous thin- film evaporator.
- the mixture which has to be distilled does surprisingly not decompose under these conditions though normally ⁇ - Acetylfuranoside begins to decompose at 150 0 C.
- step b) comprises the de-acetylation of ⁇ / ⁇ -ACF in the presence of a suitable base, followed by neutralization with a suitable acid and further followed by the re-acetylation reaction in the presence of suitable base, a suitable catalyst and a suitable acetylating agent.
- the process step a) as described above is carried out according to the specific conditions as described in the accompanying Example 1; and the process step b) is carried out according to the specific conditions as described in the accompanying Example 2.
- mother liquor means any remaining mixture of residual starting materials or by-products left over after a main reaction product is isolated from that mixture in any step according to the present method.
- mother liquor means the remaining mixture subsequent to the synthesis of ACF according to scheme 1 above, which contains residual amounts of ⁇ / ⁇ -ACF together with a variety of impurities and by-products.
- distillation or “distillation method” as used herein preferably means falling- film evaporator, molecular distillation, centrifugal molecular distillation, continuous simple distillation or related apparatus.
- a particularly preferred distillation method according to the present invention is the use of a thin-film evaporator.
- suitable solvent in connection with the crystallization of ⁇ - ACF preferably means aliphatic alcohols, most preferably propan-2-ol.
- chemical reaction step or “chemical conversion” as used herein means the conversion of the mixture of ⁇ - and ⁇ -Acetylfuranoside ( ⁇ / ⁇ -ACF), which are both present in a ratio ⁇ :B of about 1 :1, towards an increased amount of ⁇ -Acetylfuranoside by a series of chemical reaction steps, in particular by de-acetylation and subsequent re-acetylation.
- suitable base in connection with the de-acetylation in step b) as described herein means alkali hydroxides or alkali alcoholates, preferably sodium methanolate (sodium methoxide).
- suitable acid in connection with step b) as described herein means any conventional acid, preferably hydrochloric acid.
- suitable base in connection with the re-acetylation in step b) as described herein means a base, preferably aliphatic or aromatic amines, most preferably triethylamine, n- methylpiperidine or pyridine.
- suitable acetylation agent in connection with re-acetylation in step b) as described herein means acetic anhydride or acetyl halides, e. g. acetyl chloride.
- suitable catalyst in connection with the re-acetylation in step b) as described herein means substituted amino-pyridines, preferably 4-dimethylaminopyridine.
- the de-acetylation mentioned under step b) above is preferably carried out in aliphatic alcohols, in particular methanol, as solvents and at temperatures between 0 and -20 0 C, preferably -5 and -10 0 C. Subsequently, the reaction mixture is neutralized with a mineral acid, preferably hydrochloric acid, up to pH 4-6, preferably 5.
- a mineral acid preferably hydrochloric acid, up to pH 4-6, preferably 5.
- the initial solvent thus the aliphatic alcohol, is removed by distillation and replaced by a new solvent selected from chlorinated hydrocarbons, preferably methylenchloride or aromatic hydrocarbons, preferably toluene.
- re-acetylation is carried out by the addition of a suitable amine, preferably triethylamine, 4-dimethylaminopyridine and acetic anhydride at temperatures of below 30 0 C, preferably 15°C to 20 0 C.
- a suitable amine preferably triethylamine, 4-dimethylaminopyridine and acetic anhydride
- steps a) and b) are given below and in particular by the accompanying working examples.
- step c) The optional repetition of the sequential recovery cycle according to the present invention as mentioned under step c) above, can be carried out as many times as necessary. Possible limitations in the number of recovery cycles may arise from technical and chemical considerations, for example if no further ⁇ -ACF can be recovered or if the amount of recovered ⁇ -ACF becomes to small to justify the costs of the further continuation of the recovery cycle.
- the mother liquor/waste stream solvent is removed ("Desolventizing") under reduced pressure (0 to 1000 mbar, preferably 0 to 200 mbar) and at 10 to 100 0 C, preferably 30 to 80 0 C
- the obtained evaporation residue is feeded to a continuous or semi-continuous distillation as thin- film evaporator, falling-film evaporator, molecular distillation, centrifugal molecular distillation, continuous simple distillation or related apparatus.
- the use of a thin- film evaporator or molecular distillation is especially preferred.
- the residue is than distilled under reduced pressure at 0 to 10 mbar, preferably 0 to 5 mbar, and 100-210 0 C heating temperature (preferably 180-210 0 C).
- the distillate can be used and processed as crude oil or is dissolved and crystallized from organic solvent (preferably propan-2- ol).
- solvent from the initial ACF synthesis (scheme 1) is distilled off.
- a suitable solvent such as aliphatic alcohols, preferably methanol and a suitable base such as alkali hydroxides or alkali alcoholates, preferably sodium methoxide, at reaction temperatures of O 0 C to -20 0 C, preferably at -5°C to - 10 0 C.
- the reaction mixture is neutralized with an acid, preferably hydrochloric acid, up to pH 4-6, preferably 5.
- the alcohol is distilled off and the residue treated with a suitable solvent such as chlorinated hydrocarbons, preferably methylenchloride or aromatic hydrocarbons, preferably toluene.
- acetic anhydride is added slowly at batch temperatures of below 30 0 C, preferably 15°C to 20 0 C 4-dimethylaminopyridine and additionally acetic anhydride are added.
- the batch is quenched with water and a suitable solvent such as chlorinated hydrocarbons, preferably methylenchloride or aromatic hydrocarbons, preferably toluene is added.
- the organic layer is separated and the aqueous layer several times extracted with the suitable solvent mentioned above.
- the combined organic layers are washed with an alkali solution, preferably sodium bicarbonate, leading to pH 8 after washing and further washed with water.
- the solvent is distilled off and ⁇ -ACF crystallized in suitable solvents such as aliphatic alcohols, preferably propan-2-ol.
- suitable solvents such as aliphatic alcohols, preferably propan-2-ol.
- the crude product is recrystallized in a suitable solvent such as aliphatic alcohols, preferably propan-2-ol, resulting in white ⁇ -Acetylfurano side crystals with a content of ⁇ 2 weight-% of the ⁇ -anomer.
- the method described herein is also referred to as "Chemical Reprocessing" in figure 1 which further summarizes the present process. Brief Description of the Drawings
- Fig. 1 Process flow chart summarizing the process according to the present invention
- Acetylfuranoside mother liquor (ratio ⁇ / ⁇ 35:65) was evaporated to an oil (residual solvent ⁇ 1 %) at 30 to 80 0 C and 5 to 100 mbar (about 1000 kg residual oil).
- the residual oil was distilled under vacuum at 1 to 3 mbar and 200 to 210 0 C steam heating temperature in a continuous thin- film evaporator resulting in 609 kg distillate (containing ⁇ / ⁇ - Acetylfuranoside) and about 400 kg residue.
- Acetylfuranoside mother liquor (about 250 kg ⁇ / ⁇ -Acetylfuranoside) was concentrated by distillation to obtain an oily residue (ratio ⁇ / ⁇ 60:40). Then 1060 L of methanol was added and cooled to -8 0 C. 127 L of sodium methoxide was then added and stirred for 3 hours. The reaction mixture was neutralized with 126 L of semi concentrated hydrochloric acid to bring the pH to 5.1.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP10700424.4A EP2391633B1 (en) | 2009-01-27 | 2010-01-18 | Process for the recovery of beta-acetylfuranoside |
PL10700424T PL2391633T3 (en) | 2009-01-27 | 2010-01-18 | Process for the recovery of beta-acetylfuranoside |
SI201030937T SI2391633T1 (en) | 2009-01-27 | 2010-01-18 | Process for the recovery of beta-acetylfuranoside |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP09151384A EP2210895A1 (en) | 2009-01-27 | 2009-01-27 | Process for the recovery of beta-Acetylfuranoside |
EP10700424.4A EP2391633B1 (en) | 2009-01-27 | 2010-01-18 | Process for the recovery of beta-acetylfuranoside |
PCT/EP2010/050523 WO2010086247A1 (en) | 2009-01-27 | 2010-01-18 | Process for the recovery of beta-acetylfuranoside |
Publications (2)
Publication Number | Publication Date |
---|---|
EP2391633A1 true EP2391633A1 (en) | 2011-12-07 |
EP2391633B1 EP2391633B1 (en) | 2015-03-18 |
Family
ID=40801987
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP09151384A Withdrawn EP2210895A1 (en) | 2009-01-27 | 2009-01-27 | Process for the recovery of beta-Acetylfuranoside |
EP10700424.4A Active EP2391633B1 (en) | 2009-01-27 | 2010-01-18 | Process for the recovery of beta-acetylfuranoside |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP09151384A Withdrawn EP2210895A1 (en) | 2009-01-27 | 2009-01-27 | Process for the recovery of beta-Acetylfuranoside |
Country Status (11)
Country | Link |
---|---|
US (2) | US20100190976A1 (en) |
EP (2) | EP2210895A1 (en) |
JP (1) | JP5612603B2 (en) |
CN (2) | CN102245621A (en) |
CA (1) | CA2748954C (en) |
DK (1) | DK2391633T3 (en) |
ES (1) | ES2535051T3 (en) |
PL (1) | PL2391633T3 (en) |
SG (1) | SG173113A1 (en) |
SI (1) | SI2391633T1 (en) |
WO (1) | WO2010086247A1 (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2210895A1 (en) * | 2009-01-27 | 2010-07-28 | F. Hoffmann-La Roche AG | Process for the recovery of beta-Acetylfuranoside |
CN104017033B (en) * | 2014-06-14 | 2016-08-17 | 济南尚博生物科技有限公司 | A kind of method preparing glucosides |
CN112125938A (en) * | 2020-09-26 | 2020-12-25 | 安徽金禾实业股份有限公司 | Method for extracting sucralose-6-ethyl ester from sugar residues |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1135258A (en) | 1979-06-15 | 1982-11-09 | Richard D'souza | Process for the preparation of 5'deoxy-5-fluorouridine |
DE3714473A1 (en) * | 1987-04-30 | 1988-11-10 | Basf Ag | CONTINUOUS PROCESS FOR EPIMERIZING SUGAR, ESPECIALLY FROM D-ARABINOSE TO D-RIBOSE |
ITMI20032059A1 (en) | 2003-10-22 | 2005-04-23 | Clariant Lsm Italia Spa | PROCESS FOR THE PREPARATION OF DOXIFLURIDINE. |
CN100383128C (en) * | 2004-02-23 | 2008-04-23 | 上海迪赛诺医药发展有限公司 | Ramification of N-carbethoxy cytosine and preparation method and application |
WO2008080822A1 (en) * | 2006-12-29 | 2008-07-10 | F. Hoffmann-La Roche Ag | Epimerization methodologies for recovering stereo isomers in high yield and purity |
KR100908363B1 (en) * | 2007-02-28 | 2009-07-20 | 한미약품 주식회사 | Stereoselective preparation method of tri-O-acetyl-5-deoxy-β-D-ribofuranose and separation method thereof |
EP2210895A1 (en) * | 2009-01-27 | 2010-07-28 | F. Hoffmann-La Roche AG | Process for the recovery of beta-Acetylfuranoside |
-
2009
- 2009-01-27 EP EP09151384A patent/EP2210895A1/en not_active Withdrawn
-
2010
- 2010-01-18 WO PCT/EP2010/050523 patent/WO2010086247A1/en active Application Filing
- 2010-01-18 JP JP2011542848A patent/JP5612603B2/en active Active
- 2010-01-18 SG SG2011053337A patent/SG173113A1/en unknown
- 2010-01-18 EP EP10700424.4A patent/EP2391633B1/en active Active
- 2010-01-18 DK DK10700424.4T patent/DK2391633T3/en active
- 2010-01-18 SI SI201030937T patent/SI2391633T1/en unknown
- 2010-01-18 CN CN2010800035320A patent/CN102245621A/en active Pending
- 2010-01-18 PL PL10700424T patent/PL2391633T3/en unknown
- 2010-01-18 CA CA2748954A patent/CA2748954C/en active Active
- 2010-01-18 CN CN201610288682.XA patent/CN106397503A/en active Pending
- 2010-01-18 ES ES10700424.4T patent/ES2535051T3/en active Active
- 2010-01-20 US US12/690,167 patent/US20100190976A1/en not_active Abandoned
-
2012
- 2012-11-13 US US13/675,220 patent/US9580455B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
DK2391633T3 (en) | 2015-05-11 |
PL2391633T3 (en) | 2015-08-31 |
CA2748954C (en) | 2017-01-03 |
ES2535051T3 (en) | 2015-05-04 |
SI2391633T1 (en) | 2015-06-30 |
CN102245621A (en) | 2011-11-16 |
EP2391633B1 (en) | 2015-03-18 |
US9580455B2 (en) | 2017-02-28 |
US20100190976A1 (en) | 2010-07-29 |
WO2010086247A1 (en) | 2010-08-05 |
CA2748954A1 (en) | 2010-08-05 |
SG173113A1 (en) | 2011-08-29 |
JP2012513970A (en) | 2012-06-21 |
US20160333040A9 (en) | 2016-11-17 |
CN106397503A (en) | 2017-02-15 |
EP2210895A1 (en) | 2010-07-28 |
US20130072674A1 (en) | 2013-03-21 |
JP5612603B2 (en) | 2014-10-22 |
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